Obesity and insulin resistance are major causes of type 2 diabetes, representing an enormous health burden to societies worldwide. Major perturbations associated with diabetes are abnormalities in calcium homeostasis and substrate metabolism, and induction of insulin resistance. Interestingly, disruption of endoplasmic reticulum (ER) Ca2+ levels caused primarily by impaired function of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) has been demonstrated to trigger ER stress in liver and ? cell leading to the development of insulin resistance in obesity and diabetes conditions. Thus, targeting dysfunctional SERCA2 will alleviate aberrant ER stress and associated disorders in diabetes. We pharmacologically activated SERCA2b in a genetic model of insulin resistance and type 2 diabetes (ob/ob mice) with a novel class of small molecules that allosterically activate SERCA enzyme and rescue ER stress-induced cell death. These compounds are amenable to optimization for potency, and have enormous potential to treat diabetes. Studies in animal models of diabetes show significant improvement in glucose tolerance, hepatic steatosis and metabolism, and preservation of ?-cell function and survival. Through medicinal chemistry and analoging strategies, we aim in this proposal to conduct compound optimization of these novel series of SERCA activators and profile them more extensively in vitro and in vivo for further development as SERCA-based therapeutic modalities to treat diabetes and its complications.